The aldol reaction is a C—C bond forming reaction that is key to the practice of synthetic organic chemistry. For reviews of the aldol reaction, see: a) S. Masamune, et al., Angew. Chem. Int. Ed. Engl. 1985, 24, 1-30; b) C. H. Heathcock, Aldrichim. Acta 1990, 23, 99-111; c) D. A. Evans, Science 1988, 240, 420-426; d) C. H. Heathcock, et al, in Comprehensive Organic Synthesis, Vol. 2 (Eds. B. M. Trost, I. Fleming, C. H. Heathcock), Pergamon, Oxford, 1991, pp. 133-319; e) C. J. Cowden, et al., Org. React. 1997, 51, 1; f) A. S. Franklin, et al., Contemp. Org. Synth. 1994, 1, 317. As a result of its utility, intensive effort has been applied to the development of catalytic enantioselective variants of this reaction. Catalytic enantioselective aldol reactions are typically accomplished with preformed enolates and chiral transition metal catalysts (S. G. Nelson, Tetrahedron: Asymmetric 1998, 9, 357-389; A. Yanagisawa, et al., J. Am. Chem. Soc. 1997, 119, 9319-9320; E. M. Carreira, et al., J. Am. Chem. Soc. 1995, 117, 3649-3650; D. A. Evans, et al., J. Am. Chem. Soc. 1997, 119, 10859-10860; and D. J. Ager, et al., Asymmetric Synthetic Methodology (CRC Press, Inc.: Florida, 1996). Alternatively, catalytic enantioselective aldol reactions may be achieved with natural aldolase enzyme catalysts (C.-H. Wong, et al., Enzymes in Synthetic Organic Chemistry (Pergamon, Oxford, 1994); C.-H. Wong, et al., Angew. Chem. Int. Ed. Engl. 1995, 34, 412-432; and W.-D. Fessner, Current Opinion in Chemical Biology 1998, 2, 85-89). With transition metal catalyzed aldol reactions, enantioselectivity is readily reversed by exchange of the chiral ligand that directs the stereochemical course of the reaction. With enzymes, however, a general approach to the reversal of enantioselectivity is not available.
To address the problem of the de novo generation of aldolase enzymes, a strategy of reactive immunization using β-diketone haptens to program into antibodies a chemical mechanism analogous to that used by nature's Class I aldolase enzymes was developed. The chemistry of this class of enzymes is based on a unique chemically reactive lysine residue that is essential to the covalent mechanism of these catalysts. FIG. 1 illustrates a prior art hapten, viz., compound 1, having a β-diketone functionality employable as a reactive immunogen capable of trapping a chemically reactive lysine residue in the active site of an antibody. Covalent trapping was facilitated by intramolecular hydrogen bonding that acts to stabilize an enaminone in the active site of the antibody. The chemical mechanism leading up to the stabilized enaminone should match that of Class I aldolases over this portion of the reaction coordinate. Given the mechanistic symmetry around the C—C bond forming transition state, this approach allowed for the programming of this multi-step reaction mechanism into antibodies (C. F. Barbas III, et al., Science 1997, 278, 2085-2092). The efficient antibody catalysts that resulted, ab38C2 (Aldrich reagent) and ab33F12 have been shown to catalyze a broad array of enantioselective aldol and retro-aldol reactions (R. Björnestedt, et al., J. Am. Chem. Soc. 1996, 118, 11720-11724; G. Zhong, et al., J. Am. Chem. Soc. 1997, 119, 8131-8132; T. Hoffmann, et al., J. Am. Chem. Soc. 1998, 120, 2768-2779; and S. C. Sinha, et al., J. Am. Chem. Soc. 1999, submitted). For an alternative aldolase antibody strategy see J. L. Reymond, Angew. Chem. Int. Ed. Engl. 1995, 34, 2285-2287 or J. L. Reymond, et al., J. Org. Chem. 1995, 60, 6979.
What is needed is a method for increasing the repertoire of catalysts for this reaction.
In particular, antibodies with antipodal reactivity are needed. What is needed is a new hapten design concept for providing more efficient reaction programming.